The present invention relates to simple-to-manufacture and simple-to-use coatings for use on a wide variety of substrates. In one embodiment, the coatings are especially useful in conjunction with medical devices, particularly devices that may come into contact with a subject""s tissues or bodily fluids. The coatings of the present invention are thus useful in implantable or indwelling devices, as well as with devices that come into contact with a subject for a shorter period of time.
During recent years, there has been a growing emphasis in the medical field on the use of a variety of materials, including synthetic materials, in devices and apparatus that may come into contact with the body and/or bodily fluids. Examples of synthetics used in medical devices and implants include polyethylene (PE), polytetrafluoroethylene (PTFE), silicone, silicone rubber, polyurethane, Dacron, gelatin-impregnated fluoropassivated Dacron (GIF), stainless steel, polyvinylchloride (PVC), nylon, latex, polystyrene, and fluorinated ethylene-propylene copolymer, to name a few.
Many applications have been developed for the use of synthetic materials in the manufacture of devices for use in all areas of medical treatment. Devices as structurally simple as artificial ocular lenses, as well as devices as complex as dialysis machines, can all be improved or enhanced by use of the within-described coating compositions.
While the use of synthetic materials in medical devices has certain attractive structural, chemical and manufacturing advantages, the use of such materials has created several problems which have plagued medical practitioners, however. For example, while synthetic materials tend to be mechanically stable and chemically inert, they are generally not biocompatible or lubricious, especially when directly exposed to bodily fluids, particularly blood. Moreover, undesirable physiological reactions such as thrombosis or bacterial infection may result because the synthetic surfaces attract proteins and other physiological fluid components which may cause the activation of humoral and cellular components of blood. The problem tends to become more acute as storage time (or implantation time) of the device is increased.
It is well known that the insertion or implantation of medical devices such as catheters and tubing into a patient often results in irritation of the area in immediate contact with the device. The surfaces of these devices are generally not lubricious and are not readily accommodated or tolerated when inserted past or through the mucous membranes or the vascular surfaces of a patient. Thus, surgical or prophylactic application of such a device may cause bleeding, discomfort, and subsequent infection. Moreover, the insertion of devices such as chest tubes or urinary catheters tends to cause an appreciable amount of discomfort to a patient as a result of the frictional resistance encountered during insertion of the device, as well as during any subsequent movement by the patient. Therefore, a coating that enhances the ease of insertion of a medical device, thereby decreasing the risk of injury to a patient, represents an important advancement in the art as well.
Although lubricants may be used to minimize initial friction, they are difficult to keep in place and may complicate handling of the devices. Further, there may be a risk of interaction between the lubricant and the patient. Lubricants that are applied immediately before use still require additional handling by medical personnel. Moreover, some lubricants may react with a previously heparinized surface decreasing the bioactivity of the heparin and reducing its ability to prevent the formation of clots. Similarly, prelubricated surfaces may render it difficult, if not impossible, to incorporate other biocompatible substances intoxe2x80x94or coat such substances ontoxe2x80x94medical devices and apparatus, as many substances may not adhere to a lubricant-coated surface. Further, the effectiveness of a pre-applied lubricant may diminish over an extended period of time during storage. Thus, a workable solution which does not require the use of additional compounds (e.g. pre-applied lubricants) is most desirable.
Accordingly, it is an object of the present invention to overcome the problems associated with the use of existing devices by providing novel lubricious coatings as well as new methods for producing medical devices, implants, and the like that enhance patient comfort. The present invention is also readily adapted to provide coatings that reduce the risk of infection and/or thrombosis.
The present invention also provides methods for producing coated medical devices, implants, and surfaces whose coatings include bound, yet bioreactive, molecules such as lubricity-enhancing agents, antimicrobial agents, anticoagulants, antibacterials, hormones, and the like. Methods for producing multi-functional surfaces in a simple, economical manner that can be utilized in conjunction with the assembly of single- and multi-component devices are also disclosed herein.
Coatings which have enhanced lubricious qualitiesxe2x80x94as well as methods of preparing, applying and using the coatings, and the devices to which the coatings have been appliedxe2x80x94are disclosed herein. In addition, coatings which possess antimicrobial properties, antithrombotic properties, or both, are also disclosed, as are methods of preparing, applying and using such coatings.
The coatings of the present invention are sterilizable, stable, biocompatible and non-toxic, particularly during use. In addition, the coatings are durable and are able to maintain their lubricity and stability even after storage, sterilization, or both.
In a preferred aspect, this invention relates to coatings which include coupling agents and polyfunctional polymers which are able to form a crosslinked (or latticed) coating and are capable of entrapping hydrophilic and/or lubricious compounds. This capacity confers or enhances the lubricious quality of the coatings. In another aspect, this invention relates to lubricious coatings that include one or more biocompatible compounds that are capable of being coated upon or entrapped within the lattice of the coating.
In general, the present invention accomplishes these and other objectives by providing novel methods for producing devices which have stable, lubricious biocompatible surfaces. These surfaces may additionally contain other biologically active substances that make the surface even more multi-functionalxe2x80x94for example, the coatings or surfaces of the present invention may include antimicrobial and/or anti-thrombogenic compositions.
Such surfaces are produced by coating medical devicesxe2x80x94regardless of the composition of the devicexe2x80x94with unique transitional coatings formed of compositions that are wettable. As a result, the biocompatible surfaces of the present invention are lubricious and may also be designed to be antimicrobial, protein-repelling and antithrombogenic at the earliest phases of the protein cascade effect.
Thus, in one embodiment, the invention discloses a stable, lubricious, biocompatible coating composition comprising a coupling agent, a polyfunctional polymer and at least one biocompatible agent, wherein the coupling agent and the polymer interact to form a three-dimensional crosslinking network which is capable of entrapping the biocompatible agent. The coatings of the present invention are particularly useful when applied to the surface of an apparatus or device, wherein the coupling agent component of the coating is capable of chemically linking the polyfunctional polymer to the surface of a device. In various preferred embodiments, the device or apparatus is a medical device.
The invention also discloses coating compositions wherein the polyfunctional polymer has two or more functionalities, as well as compositions in which the polyfunctional polymer has an equivalent weight of 100 or less. In variations of the invention, the polyfunctional polymer is selected from the group consisting of polyethylenimine, polyvinyl alcohol, polyacrylic acid, and polyacrylamide.
In another variation of the invention, the coupling agent has an epoxy functionality of two (2) or greater. In one embodiment, the coupling agent comprises one or more epoxides. The one or more epoxides may be polyepoxides or polyglycidyl ether compounds. In embodiments where the epoxides are polyglycidyl ether compounds, they may be selected from the group consisting of diglycidyl ethers, triglycidyl ethers, and tetraglycidyl ethers.
In various embodiments of the present invention, the one or more epoxides are selected from the group consisting of sorbitol polyglycidyl ether, polyglycerol polyglycidyl ether, pentaerythritol polyglycidyl ether, diglycerol polyglycidyl ether, triglycidyl tris (2-hydroxyethyl)isocyanurate, glycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether, resorcinol diglycidyl ether, glycidyl ester ether of p-hydroxybenzoic acid, hydroquinone diglycidyl ether, neopentyl glycol diglycidyl ether, 1,6-hexancdiol diglycidyl ether, bisphenol A (PO)2 diglycidyl ether, bisphenol S diglycidyl ether, hydrogenated bisphenol A diglycidyl ether, ethylene polyethylene glycol diglycidyl ether, propylene polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, adipic acid diglycidyl ester, terephthalic acid diglycidyl ester, o-phthalic acid diglycidyl ester, and higher dicarboxylic acid diglycidyl ester.
The present invention further discloses coating compositions in which the coupling agent is selected from the group consisting of isocyanates, aldehydes and carbodiimides. In various alternative embodiments, the isocyanates are selected from the group consisting of toluene diisocyanate, diphenylmethane diisocyanate, dicyclohexylmethane diisocyanate, and hexamethylene diisocyanate.
Another variation of the present invention discloses coating compositions wherein the biocompatible agent is a hydrophilic polymer. In various embodiments, the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone (PVP), PVP/vinyl acetate copolymer, and polyethylene oxide.
In another embodiment of the invention, the biocompatible agent is an antithrombogenic or anticoagulant agent, such as heparin, heparin complex, or a heparin-like compound. In still another embodiment, the biocompatible agent is selected from the group consisting of: antibacterial (or antimicrobial) agents, antihistamines, anti-inflammatory agents, anticholinergic agents, antiparasitic agents, antiviral agents, inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, antimetabolites, anesthetics, antifungal agents, amoebicidal agents, trichomonacidal agents, analgesic agents, antiarthritic agents, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antineoplastics, antipsychotic agents, antihypertensive agents, muscle relaxants, proteins, peptides, hormones and lubricating agents.
The present invention also discloses a variety of methods, including a method of preparing a stable, lubricious, biocompatible coating on the surface of a medical device, comprising:
(a) contacting the surface with a coupling agent under predetermined conditions;
(b) contacting the surface with an admixture comprising a polyfunctional polymer and at least one biocompatible agent under predetermined conditions; and
(c) allowing the coupling agent and the admixture to interact for a time period sufficient to form a coating having a crosslinked configuration.
The invention further provides a number of predetermined conditions which are relevant to the methods disclosed herein. Thus, in one exemplary embodiment, the predetermined conditions comprise a temperature in the range of 15-95xc2x0 C.; in another embodiment, the predetermined conditions comprise a temperature in the range of 20-65xc2x0 C.
In another embodiment, the invention discloses a method of preparing a stable, lubricious, biocompatible coating on the surface of a medical device, comprising:
(a) contacting the surface with an admixture comprising a polyfunctional polymer and at least one biocompatible agent under predetermined conditions;
(b) contacting the surface with a coupling agent under predetermined conditions; and
(c) allowing the coupling agent and the admixture to interact and to form a coating having a crosslinked configuration.
In yet another variation, the invention discloses a method of preparing a stable, lubricious, biocompatible coating on the surface of a medical device, comprising:
(a) contacting the surface with a coupling agent, a polyfunctional polymer and at least one biocompatible agent under predetermined conditions; and
(b) allowing the coupling agent, the polymer and the biocompatible agent to interact to form a coating having a crosslinked configuration.
In various embodiments, the biocompatible agent is an antithrombogenic or anticoagulant agent. For example, the biocompatible agent may be heparin, heparin complex, a heparin-like compound, or any combination of the foregoing.
The present invention also discloses apparatus and devicesxe2x80x94e.g. medical devicesxe2x80x94having a stable, lubricious, biocompatible coating formed thereon, the coating comprising a coupling agent, a polyfunctional polymer and at least one biocompatible agent, wherein the coupling agent and the polymer interact to form a three-dimensional crosslinking network capable of entrapping the biocompatible agent. In one embodiment, the polyfunctional polymer is chemically linked to the surface of the medical device by the coupling agent. In various additional embodiments, the polyfunctional polymer preferably has an equivalent weight of 100 or less. In various alternative embodiments, the polyfunctional polymer is selected from the group consisting of polyethylenimine, polyvinyl alcohol, polyacrylic acid, polyacrylamide, and combinations thereof.
In another variation of the present invention, the device comprises one or more synthetic materials. Exemplary synthetic materials include plastics, composites, resins, metals, ceramics, carbonaceous materials, silicones, rubbers, polyethers, polysulfones, polyamides, polyimides, polyurethanes, polyearbonates, polyesters, polyvinylhalides, polyacrylates, polyolefins, hydrogels, and combinations thereof.
Surfaces of devices coated with the lubricious coatings of the present invention include surfaces of medical implants, indwelling medical devices, including disposable medical devices, catheters, and contact lenses, to name a few examples. This list, of course, is exemplary and not limiting.
Further objects, features and advantages of the methods, compositions and devices of the present invention, as well as a better understanding thereof, will become apparent from the following description and examples.